Japanese Electronic Study Data
Submission in CDISC Formats
Takashi Kitahara, Yuichi Nakajima, Novartis Pharma K.K
PhUSE annual conference, Barcelona
October 11, 2016
Regulatory Stream
Disclaimer
• The opinions expressed in this presentation and on the
following slides are solely those of the presenter and
not necessarily those of Novartis. Novartis does not
guarantee the accuracy or reliability of the information
provided herein.
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Agenda
1. Introduction
2. Overview
3. Key differences between PMDA and FDA
4. Suggestions for successful Japanese e-study data
submission
5. Conclusion
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Introduction
• Goals of this presentation are
– To comprehend new requirements of PMDA e-study
data submission.
– To provide tips based on actual experiences and
recent updates from PMDA.
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Key words:
e-study data submission, PMDA, FDA,
Data validation, Consultation, ARM,
Legacy data conversion, One global
process
Overview
Key date for electronic study data (e-study data)
submission for PMDA
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2016 2017 2018 2019 2020
Oct-2016~ Start accepting
e-study data
Apr-2020~ To be mandatory
E-study data submission is required,
• PMDA: Applications after Oct 01, 2016
• FDA: Studies that start after Dec17, 2016
PMDA Transitional period (3.5 years)
• Partial e-study data submission can be accepted.
• NOTE: In case of partial e-study data submission, the application will be reviewed using the conventional review process.
Transitional period (3.5 years) Partial e-study data submission
can be accepted
Overview
Scope of e-study data submission
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Mandatory • Evaluation data that provide the major basis for the
efficacy, safety, dose and administration
(i.e. results of Phase 2 and 3 studies in most cases,
including long‐term studies)
• Specific Phase 1 studies
• oncology drugs
• that have been conducted on both Japanese and
non‐Japanese subjects for ethnic sensitivity
assessment
• QT/QTc studies based on ICH E14 guideline
Case by
Case, if
requested
by PMDA
• Other Phase 1 studies
• Clinical pharmacology (CP) studies and analyses
• Integrated analysis (ISS/ISE)
Overview
Guidance provided by MHLW/PMDA
Guidance Published by Language
Japanese English
Basic Principles on Electronic Submission of
Study Data for New Drug Applications, with
Q&A document
MHLW Yes Yes
Notification on Practical Operations of
Electronic Study Data Submissions, with Q&A
document
MHLW Yes Yes
Technical Conformance Guide on Electronic
Study Data Submissions”
PMDA Yes Yes
Data Standard Catalog PMDA Yes Yes
Validation rule PMDA Yes Yes
FAQ web site PMDA Yes No
Guidance for consultation on data format PMDA Yes No
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MHLW: Ministry of Health, Labor and Welfare
Overview
Required Case report tabulation (CRT)
CRT PMDA* FDA
Datasets SDTM, ADaM SDTM, ADaM
Data guide SDRG, ADRG SDRG, ADRG
Definition file Define-XML for SDTM
Define-XML for ADaM
including ARM**
Define-XML for SDTM
Define-XML for ADaM
CRF aCRF aCRF
SAS programs Creation of ADaM
datasets and TFLs
Creation of ADaM
datasets and TFLs
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* Specific e-study data requirements for CP studies will be requested.
SDRG: Study Data Reviewer’s Guide
ADRG: Analysis Data Reviewer’s Guide
ARM: Analysis Results Metadata
TFL: Table, Figure and Listing
** differences between PMDA and FDA
Key differences between PMDA
and FDA
CDISC compliance check by Pinnacle 21
Communication / Interaction
Legacy Data Conversion
Analysis Results Metadata (ARM)
Clinical Pharmacology Study
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CDISC compliance check by Pinnacle 21
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Key Differences
1 – 5 weeks
Preparation
(Portal site) Transfer Validation NDA
Gateway
CDISC standard e-
study data - Start the validation once
PMDA receive the e-study
data
- Pinnacle 21 enterprise
version (v3.0.5)
- Specific validation criteria
Preparation for electronic
files to be submitted - e-study data
- eCTD
- Other...
Notify to PMDA - Planned application date
- Contents of deliverables
- Other...
Enter the information
about e-study data
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Key Differences
PMDA FDA
SDTM, ADaM and Define-XML SDTM, SEND
Key considerations
Three PMDA specific validation criteria which are different from FDA.
Tips
1. Executing PMDA validation at the same time as FDA validation.
2. Compatibility between validation results from Community v2.1.3 and Enterprise
3.0.5 (refer to Pinnacle 21 website).
3. No test loading environment.
CDISC compliance check by Pinnacle 21
Validation Criteria Rule
Reject PMDA will not start reviewing an application if any of
‘Reject’ errors are detected.
Error Have to explain and agree with PMDA at consultation
on data format prior to e-study data submission.
Warning To be described in SDRG/ADRG as needed.
Communication / Interaction
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Key Differences
Phase 1
Phase 2
Phase 3
NDA
Pre-
application
consultation
Consultation
end of Ph 2
Consultation
pre Ph 1
Consultation pre-
early/late Ph 2
Consultation on data format Preliminary
meeting
PMDA
Pre-NDA
meeting
End of Ph 2
meeting
End of Ph 1
meeting
Pre IND
meeting
FDA
consultation with PMDA related
to e-study data submission
Communication / Interaction
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Key Differences
PMDA FDA
Consultation on data format of
e-study data submission
Communicate by using Study data
standardization plan (SDSP)
Key considerations
Not for data assessment but for confirmation of e-study data submission contents.
Explain all validation issues categorized in “Error” on e-study data. Form 8 is required to submit to PMDA prior to consultation to inform a
summary of e-study data. Final version of Form 8 has to be submitted at NDA preliminary meeting.
Tips
1. Sorting out discussion points corresponding consultation.
2. Preparation of process guidance, roles and responsibility.
3. Consolidating feedback from each health authority.
Key differences between PMDA
and FDA
CDISC compliance check by Pinnacle 21
Communication / Interaction
Clinical pharmacology study
Analysis Results Metadata (ARM)
Legacy Data Conversion
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Clinical Pharmacology(CP) Study and
Analysis
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Key Differences
PMDA FDA
Specific data, documents are
required.
Not specifically described in Study
Data Technical Conformance Guide.
Key considerations
CP studies and analysis for e-study data submission: 1) Standard PK analysis
2) Population PK (PPK) analysis,
3) Physiologically-based pharmacokinetic model (PBPK) analysis
Tips
1. Not all of CP studies will be required for e-study data submission.
2. Communication with clinical pharmacologist.
CDISC compliant Non CDISC compliant For
ADaM System dependent data 1), 2), 3)
Define-XML Dataset definition document (PDF) 1), 2), 3)
Programs Programming specification or/and procedure
documents
1), 2)
Analysis Results Metadata (ARM)
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Key Differences
PMDA FDA
Define-XML for ADaM should
preferably include ARM.
Not required (as of September, 2016).
Key considerations
For targeted TFLs are
1) Primary and key secondary analyses,
2) Key safety analyses and
3) Dose response analyses for dose finding study.
ARM in PDF format can be acceptable.
Tips
1. Discussion on targeted analyses for ARM at clinical consultation (e.g. end
of Phase 2)
2. ARM can be considered as a part of programming activities.
Legacy Data Conversion
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Key Differences
PMDA FDA
Closed / Completed study is
possibly to be converted after
01Oct2016 (To be mandatory after
01Apr2020)
Non-CDISC compliant study which
starts after 17Dec2016 must be
followed in CDISC standards.
Key considerations
For PMDA, Same e-study data will be required as well as CDISC compliant
studies. Possibly SAS programs might be required to “reproduce” primary,
secondary and key safety results in CSR.
Tips
1. Keep traceability from converted SDTM to ADaM and traceability issues
need to be explained in SDRG/ADRG.
2. Preliminary consultation with PMDA for a reduction of workload.
Suggestions for successful Japanese
e-study data submission
• Decision of clinical data package is a key.
– In order to estimate resources for data preparation, it is recommended
to decide at an end of Phase 2 consultation.
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Which clinical
studies are
submitted
electronically?
What type of
analyses for
ADaM datasets
and ARM ?
Do we need to
submit pooled
dataset?
Suggestions for successful Japanese
e-study data submission
• One compound
can have multiple
studies with
different indication
and timing.
• Accurate
information should
be tracked as data
standard catalog
keeps updating.
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Data standard catalog
Standard 1
Standard 2
Standard 3
NDA
Study 1
(Std.1)
Study 2
(Std. 2)
Study 3
(Std. 2)
Data pooling
(Std. 3)
Indication A
• Consolidate data standards within a compound.
NDA
Study 1
(Std.1) Study 2
(Std. 1)
Study 3
(Std. 3)
Indication B
Suggestions for successful Japanese
e-study data submission
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• Consolidate data standards within a compound.
Project Study
ID
Phase /
Type of
study
Study Status
Exchange
Standards
Terminology
Standards
Indication A A101 Ph 1 / Food
effect
COMPLETED Legacy format MedDRA v8
WHO-DD 2009Mar01
A201 Ph 2 / Dose
finding
ONGOING SDTM v3.1.1
ADaM v1.0
MedDRA v14.1
WHO-DD 2010Jun01
A301 Ph 3 /
Confirmatory
ONGOING SDTM v3.1.3
ADaM v1.0
Define v1.0
...
A302 Ph 3 / long
safety
PLANNED SDTM v3.2
ADaM v1.1
Define v2.0
...
Indication B B101 ... ... ... ...
B201 ... ... ... ...
Indication C ... ... ... ... ...
Suggestions for successful Japanese
e-study data submission
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• Creating one CRT for PMDA and FDA
– Metadata Management system: to keep “metadata driven” in our process. 1. Set up data
standard with
aCRF
2. Go live in
Metadata
Management
System
3. Provide metadata into each data phase
(Data capture / Data repository /
Programming) and submission (define-
XML)
Suggestions for successful Japanese
e-study data submission
Novartis CRT creation process
• aCRF – Semi-automated process for combining each standard aCRF page.
• SDTM / ADaM – Metadata provides template programs for general domain.
• SDRG / ADRG – A template document, authoring guideline, example and training package to
keep high quality and consistency.
– Validation results for both PMDA and FDA in same section.
• Define-XML – Currently outsourcing to vendors. New internal process under investigation.
– ARM template and training package are available.
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Suggestions for successful Japanese
e-study data submission
• Collaboration between Japanese and global teams
1. Understand Japan specific requirements
– What are required for PMDA.
– One set of CRT can be prepared for both PMDA and FDA.
2. Discuss on roles and responsibility
3. Define consistent policy in advance
– To avoid big discussion for decision making and not to spend much time
for discussion.
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Conclusion
• To work effectively, global and Japan team
need to work together, share knowledge of both
FDA and PMDA requirements each other.
• E-study data submission can be beneficial not
only for us for reduction of HA inquiries, but
also for patients in terms of future drug
accessibility.
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Acronyms
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aCRF annotated CRF
ADaM Analysis Data Model
ADRG Analysis Data Reviewer’s Guide
CDASH Clinical Data Acquisition Standards
Harmonization
CDISC Clinical Data Interchange Standards Consortium
CP Clinical Pharmacology
CRF Case Report Form
CSR Clinical Summary Report
FDA Food and Drug Administration
IND Investigational New Drug
ISE Integrated Summary of Efficacy
ISS Integrated Summary of Safety
MHLW Ministry of Health, Labor and Welfare
Acronyms
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NDA New Drug Application
PBPK Physiologically Pharmacokinetic Model Analysis
PK Pharmacokinetics
PMDA Pharmaceuticals and Medical Devices Agency
PD Pharmacodynamics
PPK Population Analysis
SAS Statistical Analysis System
SDRG Study Data Reviewer’s Guide
SDSP Study Data Standardization Plan
SDTM Study Data Tabulation Model
SEND Standard for Exchange of Nonclinical Data
STS Standard Two Stage approach
TFL Table, Figure and Listing
XML Extensible Markup Language
References
• [1] FDA: Providing Regulatory Submissions In Electronic Format - Standardized Study Data
• [2] FDA: Study Data Technical Conformance Guide v3.0
• [3] PMDA: Basic Principles on Electronic Submission of Study Data for New Drug Applications
• [5] PMDA: Notification on Practical Operations of Electronic Study Data Submissions
• [4] PMDA: Question and Answer Guide Regarding “Basic Principles on Electronic Submission of Study Data for New Drug Applications
• [6] PMDA: Question and Answer Guide Regarding “Notification on Practical Operations of Electronic Study Data Submissions”
• [7] PMDA: Technical Conformance Guide on Electronic Study Data Submissions
• [8] Submitting Study Data via PMDA Gateway, Kunithio Ebi, FUJITSU, 2016 CDISC Japan Interchange
• [9] One global electronic submission, Yuichi Nakajima, Takashi Kitahara, 19th DIA Annual Workshop for Clinical Data Management
• [10] Pinnacle 21 website: https://www.pinnacle21.net/downloads
• [11] Gateway operation manual (PMDA website): https://www.pmda.go.jp/files/000213752.pdf
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Acknowledgments
• Ryan Hara (Co-Author), Principal Statistical
Programmer, BDM Statistical Programming, Novartis
• Patricia A. Majcher, Sr. Assoc. Director, Reporting Data
Stds, IQS SR Resp & EM, Novartis
• My fellow professionals who inspire us everyday.
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Thank you